The purpose of this project is to develop leads for the construction of clinically effective inhibitors of the HIV proteases, and consequently of the AIDS virus. Computer-based analyses of the active site of the HIV protease are being used as the target for an algorithm that matches the crystal structures of known compounds to that of the active site. A non-peptidic lead compound, haloperidol, has led to an effort to synthesize analogues that are more effective inhibitors of the enzyme, as well as to develop other lead structures. Mass spectrometry plays an important role in elucidation of the structures of the synthetic analogues and chemical intermediates in their synthesis. Irreversible inhibitors have also been developed. Mass spectrometry is being used with these agents to determine the nature of the alkylation process and the site of the alkylation.